The development of effective medications for the treatment of drug addiction disorders is of great importance to society. Great advances have been made in the treatment of many CNS diseases that were previously highly debilitating and essentially incurable. Cocaine addiction, however, has proven to be extremely difficult to medicate with good effect. An extensive effort has been made to develop long-acting agonists in the form of monoamine reuptake inhibitors for the treatment of cocaine addiction. Even though several promising lead compounds were developed none have proven to be broadly effective in the clinic. Thus, it is becoming clear that potential therapeutic agents interacting at other biochemical targets need to be explored. Because cocaine is an indirect agonist at dopamine (DA) and serotonin (5-HT) systems, and as a result of growing data documenting interactions between DA and 5-HT, altering 5-HT neurotransmission has been considered a viable target for pharmacotherapies. A series of recent papers have demonstrated that 5HT2A receptor antagonists may be promising therapeutic targets for attenuating the behavioral effects of cocaine. The studies proposed in this application will test the hypothesis that either highly selective 5HT2A receptor antagonists or compounds with selective 5HT2A receptor antagonism but also with some affinity to monoamine transporters will have potential as therapeutic agents for the treatment of cocaine addiction. This will be achieved through a multidisciplinary research program combining organic synthesis, medicinal chemistry, pharmacology and behavioral physiology, exploring the efficacy of a new class of 5HT2A receptor antagonists.